Hospital Medicine

Palliative care: Pain Management

I. Problem/Challenge.

Pain is a very prominent and distressful symptom in patients presenting at the end of life. In the cancer population, its prevalence is over 75% for those with advanced disease. In other palliative conditions, it is also a frequent symptom though often underestimated. A systematic review reported a prevalence of pain at 20-78% (median 41) in CHF patients, 21-77% (median 68) in COPD patients, and 21-64% (median 52) in CRF patients. Additionally, patients with neurological palliative conditions, such as stroke or ALS, may also experience significant level of pain. It has been shown that 68% of end of life stroke patients have symptoms or manifestations of pain.

II. Identify Goals with Patients.

The key points of pain management in palliative patients

The effective relief of pain in a palliative patient depends mainly on a comprehensive assessment to identify the different physical, psychological, social, and spiritual aspects that are specific to each patient, and optimally intervene on a multidisciplinary level. The pain syndrome must be assessed with detail to ascertain which components of pain prevail, as this will lead to the optimal choice of intervention (i.e., pharmacological, interventional) for each individual. Pharmacological management is one of many modalities in pain control. The choice of pharmacologic intervention should be considered in conjunction with a patient’s primary issues as well as their underlying comorbidities as all medications have distinct actions and potential side effects. Furthermore, there is variability between patients in terms of response to a particular agent.

It is important to anticipate and address concerns of pain early in the disease process for patients with terminal disease or at end of life. Anxiety and other psychosocial stressors will play a role and must also be thought of by providers.

III. Step-by-Step approach to assessment of pain in the palliative patient

A thorough assessment of the various components of pain is critical in being able to effectively manage it. The assessment should include a combination of the elements reported by the patient and/or his caregivers regarding his pain experience, as well as a physical exam, and laboratory or imaging studies appropriate to the patient’s condition.

The most important part of this assessment remains the information obtained by the patient and/or the caregivers regarding the patient’s pain syndrome. In a majority of the cases, if well conducted, this gathering of information will give many of the necessary clues in understanding the pathophysiology and other relevant components of the patient’s pain in order to initiate the most appropriate treatment.

You will need to have all the following information available in addition to the usual present and past medical and surgical history:

Pain syndrome: In assessing the symptoms, one can use the OPQRSTUV mnemonic. Onset-when did it start, was it acute or gradual and what was pattern? Provoking or Palliating- what brings it on, makes it better or worse? Quality- Identify type of pain such as neuropathic burning, tingling, numb, itchy? Radiation or region- where is the primary location and does it radiate? Severity– verbal descriptors or how severe is pain on a scale of 1-10? Treatment– what are current or past treatments and or side effects? Understanding- meaning of pain to the sufferer, total pain. Some validated and user-friendly tools may help you in this assessment such as the Brief Pain Inventory. Palliative patients often present with several pain locations and types, and each of them needs to be assessed separately.

Pain medications: Assess current regimen; start date, dosage and schedule, as described by the patient or the caregiver in charge and do not overly rely on what is in the charts as the “true regimen”, as patients do not always take medicines as prescribed. Ideally, patients and families should bring in all the pill bottles to avoid confusion or polypharmacy. Assess past regimens with dosage, mode of administration, duration of treatment, effectiveness, and side effects. Assess allergies and particular reactions. Be sure to inquire about OTC medications, including integrative or “alternative” therapies, herbal regimens, supplements and vitamins.

If you follow this checklist, you should have the background information to conduct a problem-oriented physical exam and be able to determine what lab or imaging may be required to learn more about the cause of pain, so that you are able to determine appropriate treatment options. The pharmacological options are described below; references on non-pharmacological or interventional options are available.

Pharmacological options

There are three categories of pain medications (as per the WHO pain ladder, 1986):

1) Non-opioids:

Acetaminophen: works centrally and has no anti-inflammatory action. It should be the first step of the treatment if the pain level is mild. It may also be considered a good medication to add to an opioid treatment and has been included in several prescription medications. Due to the concern of hepatic toxicity, the FDA strongly cautions against excess use of combination treatments, such as Percocet or Vicodin, with a maximum dosage limited to 325 mg of acetaminophen per dosage unit; in addition, a boxed warning will highlight potential for severe liver failure, the 1000 mg dosage will be by prescription only and the present recommendation is 625 mg acetaminophen QID maximum. The FDA has a maximum of 4 gms daily, however, this is lowered to 2 gms in liver disease and only for a limited time.

NSAIDs: may have a benefit in pain mediated by inflammation (e.g., bone metastases, musculoskeletal or skin pain) through the blockage of prostaglandins biosynthesis, which are its mediators, but their use is limited by their potential side effects, the most common ones being gastrointestinal irritation, bleeding, and renal failure. More recently, cardiac risks such as myocardial infarction and stroke have also been reported, and the FDA has strengthened their existing label warning. The options which are considered as the safest nowadays are ibuprofen and naproxen. The recommendation is to prescribe a short course of treatment (e.g., one week) and to monitor closely, especially in the cardiac and geriatric population. Proton pump inhibitors may be considered in conjunction for certain situations.

The use of COX-2 selective agents, which may have a reduced risk of GI bleeding, is not recommended in palliative care, as the dosage required to obtain an appropriate pain control should be increased to a level where the side effects are equivalent to lower doses of non-selective NSAIDs. Expense and adverse cardiovascular events have limited dramatically its use in general over the years.

2) Opioids:

The 1986 WHO pain ladder (targeting specifically cancer pain) has been a reference for a long time suggesting to step up from a non opioid to a “weak” opioid if the pain was not relieved and then only to a strong one if once again the pain control was not satisfactory. Nowadays, however, due to the usual high level of pain presented by palliative patients, and based on our deeper understanding of the pathophysiological mechanisms of pain, as well as on the increased amount of new therapeutic formulations, stronger opioids may be indicated earlier.

a) “Weak”

Codeine: converted to its active agents (among them morphine) through the enzyme CYP2D6. 10 mg codeine usually equivalent to 1 mg of morphine. However, 10% of Caucasians and 3% of Asians and African Americans are poor metabolizers and will not experience benefit of analgesic effects. Some other individuals are, on the contrary, ultra-rapid metabolizers and may have an increased risk of side effects. The only indication for codeine remains its action against cough, probably through its pro-drug.

Tramadol: synthetic opioid, about five times less potent than morphine. Not considered to be “at risk” for addiction due its weak action on the mu opioid receptors, so is not a Schedule II drug. Due to its blockage of serotonin and norepinephrine reuptake, may have an additional benefit in neuropathic pain. However, there are several limitations: a ceiling dose of 400 mg/day, an increased risk of seizures in predisposed patients, and more adverse effects than other opioids such as nausea and vomiting, especially in the geriatric population. More recently, the FDA issued a warning regarding the risk of suicidality in a population with risk factors which are very frequent in palliative care. There is also a major risk of serotoninergic syndrome due to interactions with SSRI or tricyclic antidepressants.

b) “Strong”

Morphine: remains the “gold standard” as it has been the most extensively studied, and is available in a wide range of formulations and routes. Be careful in patients with renal impairment due to one of its active metabolites, M3G, which may lead to opioid-related toxicity (please refer to the next section).

Hydrocodone: slightly less potent than morphine. Unfortunately, it is only available in combination with APAP or NSAIDs. It is metabolized to hydromorphone, and the CYP 2D6 may alter analgesic response.

Hydromorphone: similar properties than morphine but around five times more potent. It is very useful for parenteral use as it requests smaller volumes. As morphine, it has an active metabolite (H3G) which may lead to neurotoxicity at high doses or if renal impairment.

Oxycodone: synthetic opioid. Unfortunately not available as parenteral formulation. Slightly more potent than morphine (10 mg morphine=7.5 mg oxycodone). Targets not only mu receptors as other usual opioids but also kappa receptors, which explains why it may have a better action on neuropathic pain and may produce less nausea and vomiting. As only 15% is excreted through the kidneys, less risks of side effects in case of renal failure.

Oxymorphone: semisynthetic. Twice as potent as morphine, same profile of side effects. Does not induce or inhibit CYP 2D6 and 3A4.

Fentanyl: highly lipid soluble opioid which can be administered parenterally, transdermally, transmucosally, buccally, intranasally but not orally. Extremely potent (around 100 times morphine), which creates safety issues (careful to avoid confusion of its dosage in micrograms with milligrams). Please go to the next section regarding these safety issues.

Meperidine: not recommended because of the neurotoxic effects of its metabolites (increased risk of seizures in predisposed population) and its high risks of addiction. Warnings issued by the American Pain Society/Institute for Safe Medication Practice.

Methadone: synthetic opioid. Poor reputation due to the variability in half-life for individuals requiring careful titration and optimal compliance (half-life prolonged with prolonged use), its numerous interactions through metabolism by CYP3A4, 2D6 and 1A2, its cardiac risks (potential QT prolongation, ultimately torsade de pointe) and its reputation of being a medication for “drug addicts”.

It is, however, more and more recognized as a potential option due to its absence of active metabolites, the low dosages needed to obtain an efficacy (which has been demonstrated to be safe regarding potential cardiac side effects), its low cost, as well as its usefulness when the patient is allergic to other opioids. Methadone’s main benefit may be its efficacy in the treatment of chronic or neuropathic pain due to its unique action as antagonist of NMDA receptors and the blockage of the reuptake of serotonin and norepinephrine.

3) Coanalgesics or adjuvant analgesics

These medications are not considered pain medications per se, but have effects on specific types of pain syndromes, such as neuropathic or inflammatory pain. Examples are antidepressants and antiepileptic drugs. Tricyclic antidepressants are commonly used though one should be aware of side effects which may be related to antimuscarinic properties. Based on safety profile, desiprimine and nortriptyline are better tolerated with less side effects than some of the other tricyclic antidepressants. There are many positive randomized controlled trials using anticonvulsants such as gabapentin and pregabalin for pain as well. They are less effective than TCAs but have a better side effect profile and are not hepatically metabolized. The coanalgesic presenting the best efficacy level in neuropathic pain with the least side effects is gabapentin.

Corticosteroids have an indication in several conditions where inflammation is the leading cause of the pain syndrome such as neuropathic pain, cerebral edema, spinal cord compression, bone or visceral pain. Short courses of high-dose steroids are used in certain scenarios, however, ongoing treatment should be avoided due to their major side effects.

How to use these medications: questions/answers

Q: How do I start a pain treatment in a patient with a palliative condition?

A: Usually, when admitted to an acute care setting, patients with a palliative condition have already been receiving strong opioids. However, if opioid naive and needing to start pain medication in this patient population, we can consider going through the regular WHO pain ladder (non-opioids, then weak opioids, then strong opioids), but one may need to jump directly to a strong opioid.

Q: Which opioid is recommended to start a pain treatment in opioid-naive patient? At which dosage?

A: There is no evidence that a specific opioid agonist is superior to another one as first-line therapy. The agent that works for a particular patient is the ‘‘right’’ drug. It will depend on your global assessment. For a persistent somatic pain, you may use morphine or others, but a neuropathic pain may not respond as well to the usual strong opioids. Sometimes it is worth adding a coanalgesic or starting with oxycodone. The principle “start low, go slow” is a good rule of thumb. For example, you can start with 5 mg morphine (or its equivalent) as needed every 4 hours (extend the interval or decrease the dosage if renal failure or older adult). Then medicines can be titrated up as needed and tolerated based on comorbidities and other considerations of side effects such as nausea, constipation, respiratory drive, mental status, etc.

Q: Is it better to start with an immediate release (IR) form or an extended release (ER) version in an opioid-naive patient?

A: Even though an Italian study suggested that it is safe to initiate the pain treatment with an ER opioid (such as morphine ER 15 mg bid), the present consensus is still to start with an IR form. If the patient were to develop side effects, these would last for a shorter time, and will not be present for hours or even days as may be the case with a long-acting formulation. After the titration period, it is best to switch to long acting forms as soon as possible, not only to assure a constant pain control to the patient, but also to limit the highs and lows of short-acting treatments, especially intravenously. Intravenous medications are best managed by patient controlled analgesic pumps and not by IV pushes of medications to avoid variability in dosing and rush as well as its potential side effects.

Q: Where do I find a table of equianalgesic dosages for the opioids? Which one is the best?

A: Several good equianalgesic tables are available both on the internet and in various articles. However, as outlined in the title of one of the articles cited in the references – “Opioid equianalgesic tables: are they all equally dangerous?” – it is important to remember that these tables need to be used as references only. The treatment must be tailored to the patient’s specific situation and modified accordingly (i.e., elderly patient, renal or hepatic failure, signs of neurotoxicity, etc).

Q: Are parenteral forms more effective than oral ones?

A: An acute or refractory pain will of course require parenteral administration of opioids, either in bolus or in drip, with or without PCA. When the pain is controlled, you can then switch to an oral form, which will potentially allow the patient to be discharged to maintain his activities of daily living. Of note, the conversion rate from parenteral (IV) to oral is 1/3. In difficult or refractory pain syndromes, the parenteral administration may need to be maintained until the end, as well as in some gastro-intestinal conditions such an ileus. In all situations with difficult pain control, the benefits/risks of maintaining the parenteral administration or to use interventional modalities (e.g., intrathecal) if available must be carefully weighed depending on the patient’s wishes, prognosis, and present/future setting (hospice, hospital, or home).

Q: Which side effects can be anticipated?

A: Constipation is almost always present with opioid treatment and must be anticipated and addressed. The patient should be informed and given laxatives. Usually, we like to use a combination of stool softener and stimulant (such as senna and docusate sodium) and also need at times to add an osmotic laxative such as lactulose or polyethylene glycol. Always tell your patient to drink plenty of fluids. Consider methylnaltrexone for refractory opioid-induced constipation.

Nausea and or vomiting may be present in up to 30% of the patients at the initiation of the treatment of opioids and usually responds to a treatment with prochlorperazine, even though the best treatment remains a medication targeting the medulla’s chemoreceptor trigger zone such as metoclopramide (which is concomitantly an excellent prokinetic) or haloperidol (low doses, e.g., 0.5 mg bid). Ondansetron is generally not indicated except for chemotherapy-induced nausea and vomiting, and may increase the constipation and cause headaches, while also being very expensive.

Itching is present in 3% of the cases only, but is more common in the hospital setting due to the higher doses often needed. Antihistamines or rotation to another opioid may relieve the patient’s symptoms. The main side effect to be familiar with or anticipate is opioid-related neurotoxicity. This is the action of the opioid metabolites that trigger an excitatory response, with the major manifestations being confusion, allodynia, hyperesthesia, and myoclonus. If the opioid dosage is maintained or increased, the patient may become less and less comfortable, eventually developing significant pain and distress, and may even develop seizures.

One must be aware of a diagnosis known as “terminal agitation” which has numerous potential causes, one of which may be iatrogenic neurotoxicity from opiates. It is more frequent with opioids with active metabolites, such as morphine and hydromorphone, and in patients with renal failure or dehydration who cannot eliminate these metabolites and is the reason morphine and hydromorphone are not a good choice in patients with renal failure. This may be considered a “palliative emergency” due to the high level of discomfort of the patient and its iatrogenic origin. You can either decrease the dose of the opioid (about 30%) or switch to another opioid (opioid rotation) with few or no active metabolites such as oxycodone, methadone or fentanyl. Other causes may include pain, metabolic disturbances, hypercalcemia, and infection, or drug interactions.

Another potential adverse and paradoxical response to pain medications over time is known as opioid-induced hyperalgesia. This is a phenomenon where patients on long-term opiates develop a hypersensitivity and pain to noxious and even non-noxious stimuli. It can occur in palliative patients where doses of opioids are escalated too rapidly. Its mechanism is unclear but can also be alleviated with reducing or rotating treatment.

If you choose to perform an opioid rotation, the new opioid must be initiated with a lower dosage than the one of an equianalgesic equivalent (about 25% less), as there will be a period of crossover while the metabolites of the previous opioid are eliminated. Hydration is also part of the treatment, as well as temporary symptomatic treatment of confusion or myoclonus if necessary. This syndrome, if correctly managed, will resolve within 24 to 48 hours.

Q: Can I use several opioids at the same time?

A: Yes. Usually, patients would benefit from a long-acting form, but should consider having an immediate-release formulation available for potential breakthrough pain episodes when appropriate and safe for patient. It is not common to give weak and strong opioids together, however, a fentanyl patch, for example, may be supplemented by an immediate release morphine that is short-acting for break through pain. Some opioids also have specific non-pain relief-related indications. Examples include morphine or oxycodone IR targeting subjective relief of dyspnea, or methadone (low doses, e.g., 5 mg po TID) as coanalgesic in case of chronic and/or neuropathic pain.

Q: Do I have to be concerned by the risk of respiratory depression while administering opioids?

A: One should always consider comorbid conditions of sleep apnea, advanced heart or lung disease, and age of patient, but if titrated carefully, patients receiving higher doses of opioids for pain or dyspnea management should tolerate them well. Judicious use of opioids should not hasten death but one must take precautions.

Q: Can a patient be really allergic to morphine?

A: Yes, it is rare, but it may happen and is class dependent. If a patient has a real allergy to morphine, he can be switched safely to methadone or fentanyl for example. But usually, the “allergies” reported are actually side effects such as nausea, itching, or sleepiness that may have occurred in past. Still, allergies must be carefully elicited and potential side effects should be anticipated and treated properly.

IV. Common Pitfalls.

Pitfalls:

– Avoid telling patients and family “Don’t worry, the medications I give you will make you pain free.” This may give unrealistic expectations, frustrate them and harm the relationship of trust one is supposed to build. A better approach would be to say “Let’s work together to make you as comfortable as possible. It may take some time to find the best option, but we’ll go step by step”.

– Avoid lack of communication or collaboration with all healthcare providers from various disciplines to coordinate the patient’s care. Communication regarding plan upon transfer to other services, outpatient clinic, PCP, nursing home or hospice is crucial.

Medication administration-related pitfalls:

– Tell patients receiving combination forms containing acetaminophen not to take additional acetaminophen. Specify that they have to be attentive to the active ingredients in OTC cold/sleep medications to ensure they are not taking high doses or toxic doses of acetaminophen. Ensure they are aware of the maximum suggested daily dosage acetaminophen.

– Give detailed explanations to patients who start a fentanyl patch about the delayed start of onset of the medication via the patch and long effect of the medication after the patch is removed due to the delivery mechanism. Explain the effect of applying heat to the patch as it increases the absorption and risk of overdose. Patients should also be aware to seek medical advice if high grade fever.

– Remember to discuss side effects. For example, prescribing opioids without concomitant administration of laxatives may lead to severe constipation, and even in some extreme situations obstruction and the need for colostomy.

Remember to think of iatrogenic causes of terminal restlessness syndrome and paradoxical hyperalgesia and adjust medications as needed. In general, the rule of the thumb is to decrease or rotate opioids whenever suspicious of a potential opioid-related neurotoxicity or other opiate complication.

-Use a physician monitoring program. Even end-of-life patients may be getting numerous prescriptions from various providers that may cause dangerous toxicities and adverse events. Be sure that transparent conversations with patients and providers are taking place to avoid harm and that you as a prescriber are reviewing their medication history in one of these databases.

– Be sure to seek advice from pain specialists whenever you think it may help and avoid trying to manage alone if having difficulty. There are numerous modalities available in various disciplines that may benefit patients when applied in an interdisciplinary manner.

V. National Standards, Core Indicators and Quality Measures.

In summary, the major outcomes that should be considered are:

Validity and predictive capacity of assessment scales

Quality of life

Time to reduction in symptom

Incidence of adverse effects or complications from treatment or intervention

Several evidence based practices and guidelines exist from such organizations such as the US National Comprehensive Cancer Network, or the American Pain Society, or the National Consensus Project for Palliative Care among others, however, evidence suggests that pain care practices are not consistent with guideline recommendations and we can do a better job of assessing and intervening in patients with pain at the end of life.

Nabal, M. “The role of paracetamol and nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the control of pain in advanced cancer: a systematic review of the literature”. Palliative Medicine. 2011 Nov 29.